Interactions involving many different accessory molecules play an important role in regulating CD4+ T cell responses, including proliferation, differentiation and survival. Tumor necrosis factor receptor (TNFR) family members are emerging as key receptors in this regard and are implicated in both costimulation of CD4+ cell responses as well as regulation of cell survival. The main goal of this application is to establish the function of one of the less well characterized members of this family, CD27, in the regulation of CD4+ responses. First, the role of CD27 in controlling CD4+ cell proliferative responses will be studied. Purified CD4+ cells from TCR transgenic mice will be cultured with specific peptide antigen presented by transfected antigen presenting cells expressing the ligand for CD27, CD27L, and defined combinations of other accessory molecules. The requirements for and the outcome of costimulation by CD27 will be established. The possibility that, under some conditions, ligation of CD27 may lead to tolerance or death will be examined. Second, the type of cytokines induced by CD27 ligation in both primary and secondary responses will be defined and the mechanisms responsible for the apparent skewing of CD27-induced responses toward production of Th2 type cytokines will be studied. Third, the physiological role of CD27 will be investigated using in vivo models. The survival of CD27L-primed T cells upon adoptive transfer to syngeneic hosts will be monitored as well as the activity of these cells in a transgenic murine diabetes model. In addition, the potential role of CD27 in the regulation of humoral responses in vivo will be studied. Defining the role of accessory molecules in CD4+ T cell responses is of key importance in designing effective strategies for manipulation of these cells in diseases associated with inappropriate immune responses as occurs in autoimmunity and allergy.